Blood flow reductions in the heart can result in dysfunction of this organ and cell death if the flow reduction is severe enough. Restoration of coronary blood flow early during a heart attack is becoming a clinical reality with the advent and improvements in thrombolytic, mechanical, and surgical interventions. While early restoration of blood flow, for example, by thrombolysis or following transient ischemia, can prevent or mitigate the degree of cell death (infarction) occurring, reperfusion can still be associated with some degree of cardiac dysfunction or cell death (also referred to as stunned myocardia), a process begun during ischemia. Thus, it would be of great clinical value to find a means to preserve reperfusion function or cell viability of the heart and one means of doing this is to reduce the severity of ischemia before reperfusion.
Recently, a new class of compounds has been described and labeled potassium channel activators (PCA), Cook, N. S. "The pharmacology of potassium channels and their therapeutic potential," TIPS 9:21, 1988. Cook indicates "that the cellular site of action of a number of drugs used therapeutically seems to involve the modulation of membrane K[+] channels" and that "opening of K[+] channels by a new class of drugs appears to underlie their relaxation of a variety of smooth muscles" because of their ability to hyperpolarize and thus relax these cells.
Examples of such PCA drugs or compounds include (+)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine (hereinafter referred to as pinacidil) and (.+-.)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-be nzo[b]pyran-3-ol (hereinafter referred to as cromakalim or BRL 34915).
Other examples of compounds which are potassium channel activators but which have substantially weaker PCA activity include N-(2-hydroxyethyl)nicotinamide nitrate ester (hereinafter referred to as nicorandil) and 6-amino-1,2-dihydro1-hydroxy-2-imino-4-piperidino- pyrimidine (hereinafter referred to a minoxidil).
The above PCA compounds have been found to reduce blood pressure and thus may be useful as antihypertensive agents.
Sakamoto et al, Chem.Abst. 105:91027q (1986) which is based on the complete paper found in J. Nihon Univ. Med. Ass., Vol. 45, No. 4, pp 299-307 (1986), show that pinacidil administered systemically reduces arterial blood pressure in dogs subjected to myocardial ischemia, and that cardiac output increases in dogs given pinacidil compared to control animals, though contractility (function) of the heart itself is not improved as LV dp/dt is not improved. Thus, it appears that cardiac output is improved because blood pressure is reduced and thus the heart can more easily pump blood.
Imai, N., et al, "Comparative effects of nitroprusside and pinacidil on myocardial blood flow and infarct size in awake dogs with acute myocardial infarction." Circulation 77:705, 1988, discloses that pinacidil, a coronary vasodilator, given systemically, has no effect on either blood flow to ischemic myocardium or infarct size. Gross, G. J., et al, "Comparative Effects of Nicorandil, Nitroglycerin, Nicotinic Acid and SG-86 on the Metabolic Status and Functional Recovery of the Ischemic-Reperfused Myocardium, J. Cardiovascular Pharmacology, 10 (Suppl. 8):S76-S84 (1987), disclose that "nicorandil and nicotinic acid infusion prior to and during a 15-min coronary occlusion resulted in a significantly improved recovery of mycocardial segment function (%SS, dL/dt) during a 3-h reperfusion period . . . However, blood flow was more homogeneously distributed between ischemic and nonischemic regions following nicorandil treatment during reperfusion. . . " (page S83). It is believed that nicorandil's improvement of post-ischemic function is probably due to its nitrate-like action (for instance like nitroglycerin) and not due to its weak potency as a potassium channel activator (Taira, N., "Similarity and Dissimilarity in the Mode and Mechanism of Action between Nicorandil and Classical Nitrates: An Overview", J. Cardiovascular Pharmacology, 10 (Suppl. 8):S1-S9 (1987).